Pharmacological profile of 5-hydroxytryptamine-induced inhibition on the pressor effect elicited by sympathetic stimulation in long-term diabetic pithed rats

Abstract

We analysed the type and/or subtype of 5-hydroxytryptamine (5-HT) receptors involved in the inhibitory mechanisms of 5-HT on the pressor responses induced by stimulation of sympathetic vasopressor outflow in long-term diabetic pithed rats. Diabetes was induced in male Wistar rats by a single subcutaneous injection of alloxan. Eight weeks later, rats were anaesthetized, pre-treated with atropine, and pithed. The effect of 5-HT on the pressor responses elicited by stimulation of the sympathetic outflow was analysed in eight-week alloxan-induced diabetic pithed rats. 5-HT (20 microg/kg/min) reduced the pressor action obtained by electrical stimulation of the sympathetic outflow. However, there was no effect on exogenous noradrenaline-induced pressor responses. 5-CT (5 microg/kg/min), 8-OH-DPAT (5 microg/kg/min), and alpha-methyl-5-HT (5 microg/kg/min), selective 5-HT(1), 5-HT(1A) and 5-HT(2) receptor agonists, respectively, reproduced the 5-HT inhibitory action. Nevertheless, infusion of 5 microg/kg/min of 1-phenylbiguanide, CGS-12066B, L-694,247, BW273C86 or MK212 (5-HT(3), 5-HT(1B), 5-HT(1D), 5-HT(2B) and 5-HT(2C) receptor agonists, respectively) had no effect on the pressor responses elicited by stimulation of the sympathetic outflow. Methiothepin (100 microg/kg) and a cocktail of WAY-100,635 (100 microg/kg) and spiperone (125 microg/kg) blocked the 5-HT inhibitory effect on the pressor action obtained by sympathetic stimulation. Moreover, WAY-100, 635 abolished the 8-OH-DPAT inhibitory effect and spiperone blocked alpha-methyl-5-HT action. In conclusion, this study revealed that long-term experimental diabetes induces changes in the receptor type/subtype involved in the 5-HT inhibitory action on the sympathetic pressor responses produced by electrical stimulation. This is mainly mediated by pre-junctional 5-HT(1A) and 5-HT(2A) receptors.